Pancreatic cancer contributes 5% of the total cancer death in this country. It is a deadly disease but the etiology is poorly understood. Our long-term goal is to identify genetic and environmental factors that contribute to pancreatic cancer so novel preventive strategies can be developed. With an NCI grant support (RO3 CA84581), we have conducted a pilot hospital-based case-control study of pancreatic cancer. We have found a significant association between dietary exposure of heterocyclic aromatic amines (HCA) and increased risk of pancreatic cancer. We have also observed significant interactions of a number of drug-metabolizing genes and a DNA repair gene with smoking and HCA exposure. Furthermore we have detected a significantly higher frequency of micronucleus (MN) in peripheral lymphocytes of cancer cases compared to that of controls. The current proposal will build upon these results to further test the hypothesis that carcinogen exposure through smoking and dietary HCA intake increases the risk of pancreatic cancer, especially among genetically susceptible individuals. We will test this hypothesis in a hospital-based case control study with 400 cases of newly diagnosed pancreatic adenocarcinomas and 400 frequency-matched healthy controls. Cases and controls will be matched by gender, race, and age (+/- 5 years) and will be recruited from the UT M.D. Anderson Cancer Center. To identify the high-risk exposure group, we will assess the risk factor and exposure profile by using a risk factor questionnaire, a meat preparation questionnaire, and a food frequency questionnaire to collect information on smoking, alcohol, medical history, family history of cancer, and dietary history. Exposure levels of three major dietary HCA compounds as well as total HCAs will be determined in relation to cancer risk. We will determine genetic susceptibility to HCA exposure and smoking by examining the polymorphisms of several metabolic genes, i.e. CYP1A2, CYP1B1, CYP2E1, NAT1, NAT2, SUL1A1, UGT1A1 and GSTT1, and a DNA repair gene, XRCCI. We will measure the level of ENU-induced DNA adducts and frequency of MN in peripheral lymphocytes of each study participants. These biological measurements will be analyzed in relation to disease status and exposure history. Results of this study are expected to shed light on the rote of carcinogen exposure and genetic susceptibility to such exposure in the development of pancreatic cancer. Such information will be valuable for the primary prevention of this deadly disease.